1. Field of the Invention
The present invention is directed to a novel process for the synthesis of 3'-(halo-substituted)2',3'-dideoxynucleosides and 2'-(halo-substituted)2',3'-dideoxynucleosides from the corresponding anhydro-dideoxynucleoside counterparts.
2. Description of the Prior Art
Acquired Immunodeficiency Syndrome (AIDS), recognized as a systemic immunosuppressive disorder, is an infectious disease caused by a retrovirus termed human immunodeficiency virus (HIV). Since HIV is a retrovirus, viral reverse transcriptase appears to be a selective target for antiviral agents. Accordingly, a number of different reverse transcriptase inhibitors having different chemical structures have been reported to be active against HIV replication in vitro and in vivo.
Of these reverse transcriptase inhibitors, the 2',3'-dideoxyribonucleosides in particular are reported to have significant inhibitory activity against HIV in vitro (R. Dagani, Chem. and Eng. News, 41-49, Nov. 23, 1987; E. De Clercq, A. Van Aerschot, P. Herdewijn, M. Baba, R. Pauwels and J. Balzarini Nucleosides and Nucleotides, 8 (5 and 6), 659-671 (1989); A. Van Aerschot, P. Herdewijn, J. Balzarini, R. Pauwels and E. De Clercq, J. Med. Chem. 32, 1743-1749 (1989)).
Among the 2',3'-dideoxyribonucleoside products reported, 3'-azido-2',3'-dideoxythymidine (AZT), and 3'-deoxy-3'-fluorothymidine (also referred to as 2',3'-dideoxy-3'-fluorothymidine or FLT) in particular show selective anti-HIV-1 activity. The compound 3'-azido-2',3'-dideoxythymidine (AZT) is being sold commercially as a potent inhibitor of HIV-induced cytopathogenicity. However, 3'-deoxy-3'-fluorothymidine is reported to have increased activity over AZT (Balzarini, J., et al., Biochem. Pharmacol. 1988, 37, 2847; P. Herdewijn, J., et al., J. Med. Chem. 30, 1270-1278 (1987)). Accordingly, the compound 3'-deoxy-3'-fluorothymidine (FLT) and other 2'or 3'-fluoro-substituted deoxynucleosides are in particular interest as possible agents for the treatment for AIDS.
However, researchers have encountered several problems in preparing fluorinated nucleosides, including: (1) very low productivity in the existing methods of fluorination which require low concentrations of reagents and substrate and (2) minimal solubility of existing reagents in solvents normally used in the process of fluorination; and (3) inconsistent results obtained when some of the prior art processes are used.
The synthesis of FLT is known from G. Etzold, R. Hintsche, G. Kowollik and P. Langen, Tetrahedron 27 (1971) pp. 2463-2472. They describe the reaction of 2,3'-Anhydro-1-(2-deoxy-.beta.-D-xylofuranosyl)thymine with HF using AlF.sub.3 as a catalyst at 150.degree.-170.degree. to obtain the product at 28% yield. They also describe its preparation by the reaction of 3'-O-mesyl-thymidine with KHF.sub.2 or NH.sub.4 F at 190.degree. to obtain the product at 14% yield. In another reference, the authors synthesized 3'-deoxy-3'-fluorothymidine from 2,3'-anhydro-1-(2-deoxy-5-O-mesyl-.beta.-D-threo-pentofuranosyl)thymine using HF-AlF.sub.3. (J. Prakt. Chem., 315, 895 (1973).
In U.S. Pat. No. 3,775,397 the same authors report the preparation of 3'-deoxy-3'-fluorothymidine by heating the 2,3'-anhydro-1-(2-deoxy-.beta.-D-xylofuranosyl)thymine with 30 cm..sup.3 of a 4-6% solution of HF in anhydrous dioxane in a sealed vessel at 90.degree. C. to obtain the product at yields of up to 46%. Attempts to reproduce this procedure by the present inventors have not produced any appreciable amounts of the product, however.
Other closely related compounds have been fluorinated using diethylaminosulfur trifluoride (DAST). (See A. Van Aerschot, P. Herdewijn, J. Balgarini, R. Pauwels and E. DeClerq., J. Med. Chem. 32, 1743-1749 (1989))
All of these prior art references are directed to laboratory scale synthesis of the subject compounds. Attempts to produce the compounds for large scale manufacture according to the prior art procedures have proven to be unsatisfactory, however. The productivity of the prior art reactions is impractical for large scale manufacture. Very dilute concentrations of fluorinating reagents and large volumes (e.g. 0.5-1.0% for AlF.sub.3) are required as well as high temperatures due to the low solubility of the reagents. In addition, the disclosed reactions generally give rise to unisolated contaminates. Moreover, difficulties have been encountered in obtaining consistent, appreciable yields using the methods of the prior art. Reported yields with AlF.sub.3 /HF or with KHF.sub.2 or NH.sub.4 F are particularly difficult to reproduce on a consistent basis. Also, the use of some of the reagents pose a safety hazard, particularly for large scale manufacture (e.g. DAST). As a result of these problems, the prior art procedures are not well suited for large scale manufacture of the compounds of the present invention.
Accordingly, there is a need for a method of producing 2' and 3'-(fluoro-substituted)dideoxynucleosides suitable for large scale manufacture, which method circumvents the reagent solubility problems and produces good yields of the products in a consistently reproducible manner.
Surprisingly, it has been discovered that the use of a substituted organo aluminum reagent of the formula: ##STR1## wherein R, K and M are as defined below, results in a marked improvement in the productivity, yield, and operability of the reaction. In addition, a highly pure product is obtained without the need for further processing, such as chromatography. The use of the substituted organo aluminum reagent of the present invention allows the reaction to be carried out with smaller volumes and a lower temperature thereby resulting in good, consistently reproducible yields of the 2' or 3'-(fluoro-substituted)dideoxynucleosides.